B cells drive CCR5CD4 tissue-resident memory T cell cytotoxicity via IL-15Rα-IL-15 signaling in primary biliary cholangitis.

Background & Aims: IL-15Rα mediates immune responses by binding and trans-presenting IL-15 to tissue-resident memory T (T) cells, enabling sustained activation. Given the pivotal role of IL-15Rα/IL-15 signaling in autoimmune diseases, elucidating its organ-specific expression and pathogenic functions in primary biliary cholangitis (PBC) remains crucial.

Methods: Immunohistochemical staining was performed on liver tissues from patients with PBC (n=94), AIH (n=32), CHB (n=10), NASH (n=7) and HCs (n=10) to assess IL-15Rα expression. Flow cytometric analysis characterized intrahepatic IL-15Rα B cells and CD4 T cells .RNA-Seq was employed to delineate the transcriptomic signatures of in vitro-induced B cells and intrahepatic leukocytes. To investigate the cytotoxicity of T cells against cholangiocytes, we performed organoid co-culture system. Moreover, dnTGFβRII mice treated with anti-IL-15/IL-15Rα mAb were used for in-vivo validation.

Results: IL-15Rα cells were significantly increased in PBC patients, primarily concentrated within the plasmablast B cell population, and positively correlated with hepatic inflammation severity. IL-15Rα B cells enriched around bile ducts in PBC livers secrete CCL3 to recruit CCR5CD4 T cells, enhancing their effector functions via IL-15Rα/IL-15 signaling. Notably, CCR5CD4 T cells drive cholangiocyte pyroptosis through granzyme A-mediated GSDMB cleavage. Furthermore, blockade of IL-15Rα/IL-15 signaling ameliorates liver injury in PBC mouse models.

Conclusions: Our findings reveal an important pathogenic mechanism in PBC wherein IL-15Rα B cells contribute to biliary injury by activating CCR5CD4 T cells. This mechanism likely works in concert with other immune effector pathways in driving disease progression.

Impact And Implications: This study reveals that IL-15Rα-expressing B cells manifest a pro-inflammatory phenotype and promote biliary injury by impairing immune homeostasis through aberrant activation of tissue-resident memory T cells during PBC progression. Although we now offer a new paradigm how IL-15 trans-presentation is regulated in a B cell-dependent manner in PBC, the regulatory effects of IL-15Rα/IL-15 signaling on other chronic liver diseases remain to be further elucidated.